JPS6216941B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel pharmaceutically useful acetylene derivatives of amines. The compounds of the present invention can be represented by the following general formula. In the above general formula, n is an integer of 2 or 3. Also included within the scope of this invention are pharmaceutically acceptable salts and individual optical isomers of compounds of general formula. Illustrative pharmaceutically acceptable salts of compounds of the invention include inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acids, and methanesulfonic acid,
Contains non-toxic acid addition salts formed with organic acids such as salicylic acid, maleic acid, malonic acid, tartaric acid, citric acid, cyclamic acid and ascorbic acid. Among the preferred compounds of the present invention, those in which n is 2 are most preferred. Illustrative compounds of the invention are: 1-acetylene-1,4-butanediamine, 1-acetylene-1,5-pentanediamine, A compound of the general formula is a carboxylase involved in the production of polyamines that make this compound useful as a pharmacological agent. It is an irreversible inhibitor of enzymes. Polyamines, particularly putrescine, spermidine and spermine, are present in animal and plant tissues and in some microorganisms. Although the exact physiological role of polyamines has not yet been clearly delineated, there is evidence to suggest that polyamines are involved in cell division and growth. Etsuchi.
J. Williams-Atsushiman et al. (HG
Williams-Ashman et al., The Italian J.Biochem.
25 , 5-32 (1976), Air. A.Raina and J.Janne, Med.Biol. 53 ,
121-147 (1975) and Day. Etsuchi. DHRassell, Life Sciences 13 , 1635−
1647 (1973)). Polyamines are fundamental growth factors for certain microorganisms and are involved in growth processes. For example, a. Coli (E.Coli), Enterobacter (Enterobacter), Klebsiella (Klebsiella), Staphylococcus aureus), C. C. Cadaveris, Salmonella typhosa and Haemophilus parainfluenza.
parainfluenza). Polyamines have been implicated in both normal and neoplastic rapid growth in which there is increased synthesis and accumulation of polyamines following stimuli that cause cell proliferation. In addition, the level of polyamine is
patients with embryonic tissue, testes, and rapidly growing tumors;
It is known to exhibit high levels in leukemia cells, as well as other rapidly growing tissues. It is known that there is a reciprocal relationship between ornithine, S-adenosylmethionine, arginine and lysine decarboxylase activities and polyamine production. The biosynthesis of putretsucine, spermidine and spermine are interrelated. Putrescine is a decarboxylated product of ornithine, catalyzed by ornithine decarboxylase. Putretzine production can also occur by decarboxylation of arginine to produce agmatine, which is hydrolyzed to give putretzine and urea. Arginine is also involved in ornithine production through the action of the enzyme arginase. Activation of methionine by S-adenosylmethionine synthetase produces decarboxylated S-adenosylmethionine. After this, the propylamine moiety of the activated methionine can be transferred to putrescine to produce spermidine, or the polyamine moiety can be transferred to spermidine to produce spermine. Therefore, putretzcine has a role as a precursor to spermidine and spermine, and in addition, increased putretzcine synthesis is the first indication that the tissue will undergo a renewed growth process. It has been shown that it has a very controlling effect on the polyamine biosynthetic pathway. Cadaverine, a decarboxylated product of lysine, has been shown to stimulate the activity of S-adenosylmethionine decarboxylase and is known to be essential for the growth process of many microorganisms, such as Haemophilus parainfluenzae. There is. Compounds of the general formula are irreversible inhibitors of ornithine decarboxylase and lysine decarboxylase. As irreversible inhibitors of the decarboxylase enzymes listed above, compounds of the general formula are useful as anti-infectious agents effective in controlling microorganisms. For example, bacteria, molds and viruses that depend on polyamines for growth;
For example, E. coli, Enterobacter, Klebsiella, Staphylococcus aureus, Ci. C. Cadaveris, H. against viruses such as parainfluenza (H. Parainfluenza), myocarditis, herpes simplex, viruses such as smallpox virus and arbouiruses, and Semliki forest. The use of the compound of the general formula as an irreversible inhibitor of ornithine and S-adenosylmethionine decarboxylase in vivo can be demonstrated as follows. An aqueous solution of the appropriate compound of the formula is administered orally or parenterally to male mice or rats. Animals are sacrificed 1 to 48 hours after administration, and the ventral lobe of the prostrate is removed and homogenized using ornithine or S-adenosylmethionine carboxylase activity. This activity is generally described as a. A. Peg (EAPegg)
and Etsuchi. J. HG Williams-Ashman Biochem.J. 108 , 533
-539 (1968) and Zei. J.ja¨nne and H. J. Williams-Atsushiman (H.
G. Williams−Ashman), Biochem and Biophys.
Res.Comm. 42 , 222-228 (1971). To administer compounds of the general formula, trans (±)-2-phenylcyclopropoamine or N-
At the same time, a monoamine oxidase inhibitor such as benzyl-N-methyl-2-propynylamine,
Preferably, the administration is by well known methods. Compounds of the general formula are metabolic precursors of compounds of the structure: where n is an integer 2 or 3, and this compound is known to be an irreversible inhibitor of gamma-aminobutyric acid transaminase and, when administered, results in high levels of gamma-aminobutyric acid (GABA) in the brain. arises as Compounds of the above formula as precursors of γ-acetylene γ-aminobutyric acid can be used to treat Huntington's disease, Parkinson's syndrome, extrapyramidal effects of drugs, e.g. neuroleptic acute attack disorders with epilepsy,
It is useful in the treatment of central nervous system disorders consisting of alcohol withdrawal, barbiturate withdrawal, psychosis associated with schizophrenia, depression, depressive disorders and involuntary movements associated with hyperkinesia. Yay. Y. Godin et al., Journal Neurochemistry,
16, 869 (1969), several previous studies have shown that γ-aminobutyric acid is the main inhibitory propagator in the central nervous system. Mutaku disease (The Lancet, November 9, 1974, PP1122−
1123), can lead to disease states such as Parkinson's syndrome, schizophrenia, epilepsy, depression, hyperkinesia and depressive diseases (Biochem,
Pharmacol. 23, 2637-2649 (1974)). That the compound of the general formula is metabolically converted to the compound of the formula is demonstrated by the protective effect of this compound against acute audiogenic seizures in mice of the DBA strain. This is shown by Simler et al., Biochem.Pharmacol.22, 1701.
(1973) in a general manner, and this method is used today for evidence of anti-epileptic activity. Compounds of the general formula are useful as antibiotics and as chemical intermediates in the production of new cephalosporin derivatives having the structure: In the formula _{, Z2} is _H2NCH2- ( _CH2 )n-, and n is 2
Or 3. The compounds of the general formula and their pharmaceutically acceptable salts as well as the individual optical isomers are new compounds useful as antibiotics and are treated in a similar manner to many well-known cephalosporin derivatives such as cephalexin, cephalothin and cephaloglycine. Can be administered. Compounds of general formula and their pharmaceutically acceptable salts and optical isomers can be administered orally or parenterally and topically to warm-blooded animals, i.e. birds and animals such as cats, dogs, cattle, sheep, horses and humans. It can be administered alone or in the form of pharmaceutical preparations. For oral administration, the compounds can be administered in the form of tablets, capsules or pills, elixirs, suspensions. For parenteral administration, the compound is best employed in the form of a sterile aqueous solution that may contain sufficient salt and other solutes, such as glucose, to make the solution isotonic. For topical administration, compounds, salts and isomers of the general formula can be mixed into creams and ointments. Exemplary bacteria in which compounds of the general formula, their pharmaceutically acceptable salts, and individual enantiomers are active are Staphylococcus aureus, Salmonella schotmuehleri, and Klebsiella niumoniae.
pneumoniae), Diplococcus pneumoniae, Streptococcus pyogenes
It is. Pharmaceutically acceptable non-toxic inorganic acid addition salts of compounds of general formula are mineral acid addition salts such as hydrochloride, hydrobromide, sulfate, sulfamate, phosphate; organic acid addition salts include e.g. Maleate, acetate, citrate, oxalate, succinate, benzoate, tartrate, fumarate, malate and ascorbate. Salts can be produced by conventional methods. Illustrative compounds of the general formula are 7-[[2
-[4-(1-acetylene-4-aminobutylamino-methyl)phenyl]acetyl]amino]-3
-Acetyloxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]octo-2
-ene-2-carboxylic acid, [octo is the translation of Cct]
and 7-[[2-[4-(1-acetylene-5-aminopentylaminomethyl)phenyl]acetyl]-amino]-3-acetyloxymethyl-8-
Oxo-5-thia-1-azabicyclo[4.
2.0]-oct-2-ene-2-carboxylic acid. The method for producing the compound of the general formula will be described below. As pharmacologically useful agents, compounds of the general formula can be administered to the patient being treated in a variety of ways to obtain the desired effect. The compounds can be administered alone or orally, parenterally - for example intravenously, intraperitoneally, subcutaneously or topically - in the form of pharmaceutical preparations. The amount of compound administered varies over a wide range and can be any effective amount. Depending on the treatment condition of the patient being treated and the mode of administration, the effective amount of the compound to be administered will vary from about 0.1 mg/Kg to 500 mg/Kg of patient's body weight per unit dose, preferably about 10 mg/Kg of patient's body weight per unit dose. /Kg to approximately 100mg/Kg. For example, a typical dosage form is a tablet containing 10 to 300 mg of a compound of formula, which may be administered to a patient being treated from 1 to 4 times per day to obtain the desired effect. As used herein, the term patient is taken to mean warm-blooded animals such as mammals, such as cats, dogs, rats, mice, guinea pigs, horses, cows, sheep and humans. The solid unit dosage form may be of the conventional type. The solid form can be a capsule, which can be of the conventional gelatin type, containing a compound of the invention and a carrier, such as a lubricant and an inert filler such as lactose, sucrose or cornstarch. In other embodiments, the new compound may be used as a binder such as gum arabic, cornstarch or gelatin, as a disintegrant such as cornstarch, potato starch or alginic acid, and as a lubricant such as stearic acid or magnesium stearate. In combination with lactose,
It is made into tablets using conventional tablet bases such as sucrose or cornstarch. For parenteral administration, the compound may be prepared in a physiologically acceptable form with a pharmaceutical carrier, which can be a sterile liquid, such as water or oil, with or without the addition of surfactants or other pharmaceutically acceptable excipients. The injectable dosage may be administered as a solution or suspension of the compound in an acceptable diluent. Illustrative oils used in these formulations are oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil. In general, water, saline, aqueous dextrose and related sugar solutions, ethanol and glycols such as propylene glycol or polyethylene glycol are desirable liquid carriers, particularly for injectable solutions. The compounds can be administered in the form of depot injection or filler preparations, which can be formulated in a manner to permit sustained release of the active ingredient. The active ingredient is compressed into tablets or small cylinders and implanted subcutaneously or intramuscularly as a depot injection or implant.
Implants are made from biologically degradable polymers such as synthetic silicones - such as Dow Corning.
An inert material such as Silastic-, a silicone rubber manufactured by Corning Corporation, is used. Compounds of the general formula are:
It is made by treating an appropriately protected propargylamine derivative with a strong base. This intermediate is an alkylating reagent of the formula R ₃ X, where X is a halogen such as chlorine or bromine and R ₃ is
PhHC = NCH ₂ (CH ₂ )n-, where n is an integer 2 or 3), and then the protecting group is removed by hydrolysis as shown in the following reaction scheme. . In the above reaction scheme, R ₃ and X have the meanings as previously defined herein. Rh represents phenyl, R ₅ is hydrogen, methoxy or ethoxy, R ₆ is phenyl, tert-butyl,
triethylmethyl, 1-adamantanyl or 2-
Frill, but when R ₅ is hydrogen, R ₆ is 1
- provided that it is not adamantanyl or 2 _- furyl; can be,
Z′ ₁ is β-methylthioethyl, β-benzylthioethyl or

[Formula], n is an integer 2 or 3. Suitable strong bases that can be used in the above reaction to form carbanions include alkyllithiums such as butyllithium and phenyllithium, lithium di-alkylamides such as lithium diisopropylamide, lithium amide, tertiary potassium butyrate, It removes a proton from the carbon atom adjacent to the acetylene moiety, such as sodium amide. The alkylating reagents R ₃ X used in the above reactions are well known in the art or can be made by methods known in the art. reactant

Reactants in which R ₁ in the formula is hydrogen include, for example, 3-bromo-n-propylamine hydrochloride or 4-bromo-n-butylamine hydrochloride, benzaldehyde and an organic amine such as triethylamine, diethyl ether, tetrahydrofuran, etc. It can be made by reaction in an ether such as dioxane, a solvent such as chloroform or dichloromethane. The alkylation reaction may be carried out in a neutral solvent such as benzene, toluene, ether, tetrahydrofuran, dimethylsulfoxide, hexamethylphosphortriamide. The reaction temperature is about -
The angle varies from 100° to 25°, preferably about -70°, and the reaction time varies from about 1/2 hour to 24 hours. In the step from compound 2 to the compound of formula, removal of the protecting group is accomplished by treatment with an aqueous acid, e.g., hydrochloric acid, followed by treatment with a base, e.g., sodium or potassium hydroxide, as shown in the reaction scheme. This is achieved by treatment with an aqueous solution or treatment with phenylhydrazine, hydroxylamine or hydrazine followed by treatment with an aqueous base solution. Propargylamine derivatives, compound 1 in which R ₅ is hydrogen, are made by adding protecting groups on the acetylene function and on the nitrogen function of propargylamine. Protection of the nitrogen functional group of propargylamine can be achieved in a well-known manner by forming Schiff's base with a compound having a non-enolized carbonyl selected from benzaldehyde, 2,2-dimethylpropanal and 2,2-diethylbutanal. achieved by. Protection of the acetylene function can be achieved by converting the Schiff base described above with trimethylsilyl chloride or triethylsilyl chloride, where the alkyl moiety has 1 to 4 carbons and is linear or branched, yielding the corresponding trialkylsilyl derivative. This can be achieved by reacting with various trialkylsilyl chlorides. The propargylamine derivative of compound 1 in which R ₅ is a methoxy group or an ethoxy group is
Propargylamine, in which the acetylene function is protected by a trialkylsilyl group and the alkyl moiety has 1 to 4 carbon atoms and is straight or branched, is reacted at 0°C with diethyl ether, dioxane, benzoyl chloride, pivalic acid chloride, or 2,2-diethyl-butyric acid chloride, 2 in the presence of an organic base such as triethylamine or pyridine in tetrahydrofuran, chloroform, methylene chloride, dimethylformamide, dimethiacetamide, or benzene chloride. - react with furancarboxylic acid chloride or 1-adamantanecarboxylic acid chloride, after which the reaction mixture is reacted with about 25
Produced by heating to ℃. The resulting amide derivatives are methyl fluorosulfonate, dimethyl sulfate, methyl iodide, methyl p-toluene sulfonate, trimethyloxonium hexafluorophosphate when R ₅ is a methoxy group, or trimethyloxonium hexafluorophosphate when R ₅ is an ethoxy group. When combined with an alkylating reagent such as triethyloxonium tetrafluoroborate at about 25°C in a chlorinated hydrocarbon solvent such as methylene chloride, benzene chloride or chloroform, the reaction mixture has a reaction temperature of about 12-20°C. Refluxed for an hour.
The mixture is then cooled to about 25°C, an organic base such as triethylamine or pyridine is added,
After this, the solution is extracted with brine and the product is isolated. The protected propargyl amine starting material is a 3-trialkylsilylprop-2-ynyl-1-iminobenzyl derivative, i.e., compound 1, where R ₅ is hydrogen and R ₆ is phenyl, and is heated with hydrazine for about 1/2 hour at about 25°C. Alternatively, it can be obtained by treatment with phenylhydrazine. After this, the mixture is diluted with, for example, petroleum ether, benzene, toluene, and the iminobenzyl derivative is isolated. Imin instead
Hydrolyzed with 0.5-1N HCl and the aqueous layer is evaporated to give the amine hydrochloride. Alternatively, compounds of the general formula are prepared as follows. n-Butyllithium (50ml of 2M solution,
0.1M) in 1 part of tetrahydrofuran at -78°C are added 21.5g (0.1M) of 3-trimethylsilylprop-2-ynyl-1-iminobenzyl. After this, 15.7g (0.1M) of bromochloropropane is added and the solution is kept at -30°C for 2 hours. The reaction mixture is then treated with water and extracted with ether. Ether extract is
It is evaporated and leaves a residue, the residue is 18.5g.
(0.1 M) of potassium phthalimide in 100 ml of dimethylformamide (DMF).
Heated at 100°C for 3 hours. DMF under reduced pressure (12
mm), the residue is taken up in ether, washed with water, dried over magnesium sulphate and evaporated. The oily residue in 300 ml ethanol is treated with 10 g (0.2 M) hydrazine hydrate at reflux overnight. After this, the solvent is evaporated leaving a residue which is treated with an aqueous base and extracted with an organic solvent leaving a residue which is heated with 200 ml of 6N hydrochloric acid for about 10-48 hours. The aqueous solution is extracted with methylene chloride, made alkaline, and then extracted again with methylene chloride. The organic solution is concentrated and the residue is the product i.e. 1-acetylene-1,4-butanediamine (boiling point 50°C/0.4mm)
distilled to give The optical isomer of the compound of the general formula uses carbalkoxyphthalimidate, in which the alkoxy moiety is a linear or branched lower alkoxy group having 1 to 4 carbon atoms, in an ether or lower alcohol; By protecting the terminal amine against acetylene as a phthalimide derivative, R. Viterbo et al.
Resolution can be achieved using (+) or (-) binaphthyl phosphoric acid by the method of Tetrahedron Letters 48, 4617 (1971), or by using (+) camphor-10-sulfonic acid followed by treatment with hydrazine. Individual optical isomers of compounds in which R _a , R _b are other than hydrogen can be obtained starting with a simply resolved amine or resolved phthalimide derivative as described herein for the racemeate. A compound with the general formula is a compound with the following formula: (wherein Y and M have the meanings defined in the general formula, and this compound is
, which is incorporated herein by reference. ) in which R _a , R _b are hydrogen and the terminal amino group to the acetylene function is protected by a suitable blocking group such as tert-butoxycarbonyl. The reaction is generally carried out in a lower alcohol such as methanol, ethanol or iso-propyl alcohol, or in a solvent such as dimethyl sulfoxide, dimethyl formamide or an aqueous mixture of these solvents. The reaction temperature may vary between about 0<0>C and 125<0>C and the reaction time may vary between 1/2 and 24 hours. Following the solvolysis reaction, the amino protecting group is removed by acid hydrolysis and the cephalosporin product is isolated in a conventional manner. Reference Example 1 below illustrates the use of a compound of the general formula (R _a and R _b are hydrogen) as a chemical intermediate in the preparation of a cephalosporin of the formula. Reference example 1 7-[[2-[4-(1-acetylene-4-aminobutylaminomethyl)phenyl]-acetyl]
amino]-3-acetyloxymethyl-8-oxo-5-thia-1 azabicyclo[4.2.
0] Oct-2-ene-2-carboxylic acid 1 g of 3-acetyloxymethyl-7-[[2-
[4-(chloromethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 1 g of 1-acetylene-1・4-Butanediamine (terminal amino group to acetylene functional group is protected with tert-butoxycarbonyl)
A mixture of 50ml of ethanol was stirred at 25°C for 24 hours. After this, the solvent is removed leaving a residue. The residue was treated with mild acid and chromatographed on silica gel using benzene-acetone as eluent.
-[4-(1-acetylene-4-aminobutylaminomethyl)phenyl]-acetyl]amino-3-
Acetyloxymethyl-8-oxo-5-thia-
1-Azabicyclo-[4.2.0]Octo-2-
Gives ene-carboxylic acid. Reference Example 2 An exemplary composition for a hard gelatin capsule is as follows. (a) 1-acetylene-1,4-butanediamine
20mg (b) Talc 5mg (c) Lactose 90mg A prescription is made by passing the dry powders of (a) and (b) through a fine mesh screen and mixing well. This powder is then poured into hard gelatin capsules per capsule.
Packed with 115mg net fill. Reference Example 3 The composition for tablets is as follows. (a) 1-acetylene-1,4-pentanediamine
20mg (b) Starch 43mg (c) Lactose 45mg (d) Magnesium stearate 2mg Lactose is mixed with compound (a) and part of starch, granulated with starch paste, and the resulting granules are dried.
Screen and mix with magnesium stearate. This mixture is compressed into tablets of 110 mg each. Reference Example 4 An exemplary composition of an injection suspension is a 1 ml ampoule for intramuscular injection as follows. Weight percent (a) 1-acetylene-3-methylthiopropylamine 1.0 (b) Polyvinylpyrrolidone 0.5 (c) Lecithin 0.25 (d) Water for making an injection 100.0 Mix the substances in (a)-(d); After homogenization, fill into a 1 ml ampoule, seal the ampoule, and heat at 121℃.
Autoclave for 20 minutes. Each ampoule contains 10 mg per ml of fresh compound (a). Example 1 1-acetylene-1,4-butanediamine 10.8 g in 500 ml of tetrahydrofuran
(0.05M) of 3-trimethylsilylprop-2-
To the inyl-1-iminobenzyl is added n-butyllithium (0.05M) at -78°C under nitrogen pressure. Ten
After minutes the dark red carbanion is treated with 11.3 g (0.05 M) of 3-bromopropyl-1-iminobenzyl in 20 ml of tetrahydrofuran. 3 at -78℃
After standing for a period of time, 50 ml of water is added and the tetrahydrofuran is evaporated leaving a residue. The residue is heated under reflux with 100 ml of 6N hydrochloric acid for 48 hours under a nitrogen atmosphere. After cooling, the aqueous solution is washed with methylene chloride, made alkaline with aqueous sodium hydroxide and re-extracted with methylene chloride. The methylene chloride extract is dried over magnesium sulfate, filtered, concentrated and distilled to give 1-acetylene-1,4-butanediamine (boiling point 50°C/0.4mm). The dicyclamate salt of 1-acetylene-1,4-butanediamine is obtained by dissolving the diamine in methanol and adding 2 molar equivalents of Cyclamic acid. The solution was concentrated, after which ether was added and the precipitate formed, i.e. 1-acetylene-1.4-
Collect the disyclamate salt of butanediamine.
Dihydrochloride is obtained by treating the diamine with aqueous hydrochloric acid, evaporation and recrystallization from methanol. Melting point is 173°C. Reference example 5 3-bromopropyl-1-iminobenzyl 3-bromopropyl-1 used in Example 1
- The iminobenzyl derivative was obtained by adding 21.2 g (0.2 M) of benzaldehyde and 20.2 g (0.2 M) of triethylamine to 43.6 g (0.2 M) of 3-bromopropylamine hydrobromide in 300 ml of methylene chloride. It will be done. The mixture is stirred at room temperature overnight, after which the solvent is removed on a rotary evaporator and the residue is treated with ether. The ether solution was filtered, the filtrate was dried over magnesium sulfate, filtered, concentrated, and distilled to give 3-bromopropyl-1-iminobenzyl (boiling point 110°C/0.5mm).
get. Reference example 6 1-acetylene-3-benzylthiopropylamine 21.5 in 400 ml of tetrahydrofuran at -78°C
g (0.1M) of 3-trimethylsilylprop-2
A solution of -ynyl-1-iminobenzyl is treated with n-butyllithium (50 ml of a 2.0 M solution, 0.1 M). After this 18.6g in 20ml tetrahydrofuran
(0.1M) S-benzyl-2-chloro-ethanethiol is added and the solution is maintained at -30°C for 15 hours. The mixture is washed with brine, extracted with ether and the ether extract is evaporated leaving a residue.
This residue is treated with 400 ml of a 2M solution of aqueous hydrochloric acid and refluxed for 12 hours. The aqueous solution is thoroughly washed with methylene chloride, made alkaline with potassium carbonate, and then extracted again. After drying the organic solution over magnesium sulfate and filtering, the filtrate is concentrated.
The resulting residue was distilled under high vacuum and 1-
Acetylene-3-benzylthiopropylamine is obtained. This is purified as a hydrochloric acid addition salt. Reference Example 7 1-acetylene-3-methylthiopropylamine In the process of Example 7, S-benzyl-2-
When an appropriate amount of S-methyl-2-chloroethanethiol is used instead of chloroethanethiol, 1-
Acetylene-3-methylthiopropylamine is obtained. Reference example 8 5'-desoxy-5'-[S-(3-acetylene-
3-aminopropyl)-S-(methyl)-thio]
Adenosine To 10mM sodium amide in 200ml ammonia is added 10mM 1-acetylene-3-benzylthiopropylamine prepared in Example 7. 1
After the time, add sodium metal in small pieces until the blue color persists for 5 minutes. After this, 10mM 2′・
Add 3'-isopropylidene-5'-p-toluene-sulfonyladenosine. After 2 hours, the ammonia is evaporated and the residue is treated with 1N sulfuric acid at 25° C. for 48 hours. Subsequently, the pH was adjusted to 6, and the solution was applied to an ion exchange resin KV−2NH ₄ ⁺ .
Apply to DEAE cellulose (OH ^- ) column. The aqueous eluent is evaporated and the residue is recrystallized from water/ethanol to give 5'-desoxy-5'-(3-acetylene-3-aminopropylthio)adenosine. Add 4 ml of acetic acid and 4 ml of adenosine derivative.
of formic acid and add 1 ml of methyl iodide. The mixture is maintained at 25°C under nitrogen pressure for 6 days, after which the solvent is removed under vacuum at 25°C. The resulting residue is dissolved in 8 ml of 0.1N hydrochloric acid and a saturated aqueous solution of Reineke's salt is added. The resulting precipitate is collected and treated with 1.5 g of silver sulfate in acetone for 36 hours at 25°C. Insoluble residue is removed by filtration and washed with methanol. The combined filtrate was filtered under reduced pressure to obtain 5'-desoxy-
5'-[S-3-acetylene-3-aminopropyl)-S-(methyl)thio]adenosine is obtained. Reference Example 9 N-(1-acetylene-4-guanidinobutyl)acetamide 1.54 g (10
3.7 g (20 mM) of ethylisothiouronium hydrobromide are added to a solution of N-(1-acetylene-4-aminobutyl)acetamide (mM). The pH of the solution is maintained at 10 by adding 2M sodium hydroxide for 48 hours at 25°C.
After this time the methanol is evaporated and the aqueous solution is thoroughly extracted with dichloromethane. The organic layer is dried and evaporated to yield N-(1-acetylene-4-guanidinobutyl)acetamide. In the above procedure, N-(1-acetylene-4
When an appropriate amount of benzyl N-(1-acetylene-4-aminobutyl) carbamate is used in place of benzyl N-(1-aminobutyl)acetamide,
-acetylene-4-guanidinobutyl) carbamate is obtained. This was combined with HBr in dioxane (40
% (w/w) solution) for 30 minutes at 28°C, ether is added and the precipitated 1-acetylene-4-guanidinobutylamine is collected. Reference example 10 N-(4-acetylene-4-aminobutyl)-2
-Aminopropionamide 492 mg (2mM) N in 4ml dichloromethane
-(1-acetylene-4-aminobutyl)benzyl carbamate solution at 25°C for about 15 hours.
After treatment with 446 mg (2mM) of N-carbobenzoxyalanine and 412 mg (2mM) of N.N'-dicyclohexylcarbodiimide, the solution is cooled to 0°C and the precipitated dicyclohexylurea is filtered off. Dilute the filtrate with 20 ml of dichloromethane.
Wash with 1N hydrochloric acid, water and aqueous sodium bicarbonate, then dry and concentrate. The resulting residue was heated to 25°C.
The N-(4-acetylene-4-aminobutyl)-2-aminopropionamide dihydrohydrogen precipitated by treatment with 6 ml of a 40% (wt/wt) hydrogen bromide solution in dioxane for 30 min, then diluted with ether. Collect bromides. Reference example 11 N-(4-acetylene-4-aminobutyl)acetamide hydrobromide 492 mg (2mM) of N-(1
-acetylene-4-aminobutyl)-benzyl carbamate is treated with 202 mg (2 mM) of triethylamine followed by 160 mg (2.1 mM) of acetyl chloride. After 1 hour at 25°C, the solution is washed with water, dilute hydrochloric acid and aqueous sodium carbonate solution, dried and concentrated. The resulting residue was treated with 6 ml of 40% (W/W) hydrogen bromide solution at 25° C. for 30 minutes and ether was added to precipitate N-(4-acetylene-4-aminobutyl)acetamide hydrobromide. Collect. In the above procedure, if an appropriate amount of ethyl chloroformate is used instead of acetyl chloride, N-(4-acetylene-4-aminobutyl)-
Ethyl carbamate is obtained. Reference example 12 N-(1-acetylene-4-aminobutyl)acetamide 242 mg (1 mM) of N- in 10 ml chloroform
A solution of (4-acetylene-4-aminobutyl)phthalimide was added to 1 ml of triethylamine, followed by
Treat with 78 mg (1 mM) acetyl chloride in ml chloroform. After 1 hour, the solution is washed with water, dried and concentrated at 25°C. The residue obtained is dissolved in 10 ml of ethanol and treated with 60 mg (1.1 mM) of hydrazine hydrate at reflux for 2 hours, after which the solvent is evaporated. The residue is treated with 1N sodium hydroxide until the solid is dissolved and extracted with dichloromethane. The organic layer was dried and concentrated to give N-(1-acetylene-
4-Aminobutyl)acetamide is obtained. N-(4-acetylene-4-aminobutyl)phthalimide used in the above process is produced as follows. 13.5g in 70ml tetrahydrofuran
A solution of 6.91 g of carbethoxyphthalimide (61.6 mM) in 30 ml of tetrahydrofuran in an ice bath.
(61.6mM) of 1-acetylene-1,4-butanediamine. After the addition is complete, reduce the mixture to 25%
After stirring for 2 hours at °C and diluting with ether, the solution is extracted with 1N hydrochloric acid (3 x 100 ml). The aqueous layer was washed several times with ether and concentrated to dryness leaving a residue.
This was recrystallized from ethanol to produce N-(4-acetylene-4-aminobutyl)phthalimide HCl.
is obtained, which is converted into the free base by well-known methods. During the process of Reference Example 12, when a suitable amount of ethyl chloroformate is used in place of acetyl chloride, N-(1-acetylene-4-aminobutyl)-ethyl-carbamate is obtained. In the process of Reference Example 12, when an appropriate amount of benzyl chloroformate is used instead of acetyl chloride, N-(1-acetylene-4-aminobutyl)-
Benzyl carbamate is obtained. Reference example 13 N-(1-acetylene-4-aminobutyl)-2
-Aminopropionamide 450 mg (2mM) N- in 10ml dichloromethane
202mg (2m) of carbobenzoxyalanine solution
M) trimethylamine followed by 218 mg (2 m
M) with ethyl chloroformate. twenty five
After 1 hour at °C, the solution was dissolved in 484 mg (2 mM) of N-(4-acetylene-
Treat with 4-aminobutyl)phthalimide and maintain at 25°C for 1 hour. After this time the solution is washed with 1N hydrochloric acid, water and aqueous sodium carbonate, dried and concentrated. Dissolve the residue in 15 ml of ethanol and add 2
100 mg of hydrazine hydrate (2 m
After treatment with M), the solvent is evaporated. 5% residual
Treat with aqueous sodium hydroxide solution and extract with dichloromethane. The organic layer is dried and concentrated and the resulting residue is treated with 5 ml of a 40% (w/w) hydrogen bromide solution in dioxane. After 30 minutes at 25°C, the mixture is treated with ether and the precipitated N-(1-acetylene-4-aminobutyl)-2-aminopropionamide dihydrobromide is collected. Reference example 14 1-acetylene-1,4-butylene-bis-2
-Aminopropionamide 900 mg (4mM) N- in 10ml dichloromethane
405mg (4m) of carbobenzoxyalanine solution
M) triethylamine followed by 435 mg (4 m
M) with ethyl chloroformate. twenty five
After 1 hour the solution was dissolved in 5 ml dichloromethane at
Treat with 224 mg (2mM) of 1-acetylene-1,4-butanediamine. The solution is kept at 25° C. for 1 hour, then washed with water, dried and concentrated. The resulting residue was diluted with 40% (W/
W) Treatment with 6 ml of hydrogen bromide solution and then dilution with ether. Collect the precipitate and add 1-acetylene-1.
4-Butylene-bis-2-aminopropionamide dihydrobromide is obtained. Reference Example 15 1-Acetylene-1,4-butylene-bis-acetamide A solution of 0.5 (4.5mM) of 1-acetylene-1,4-butanediamine in 50ml of ether containing 0.91g (9.0mM) of triethylamine was mixed with 0.7 g
(9.0 mM) acetyl chloride. After 1 hour, the ether solution is washed with brine, dried and evaporated to give 1-acetylene-1.4-butylene-bis-acetamide. In the above process, if an appropriate amount of ethyl chloroformate is used instead of acetyl chloride, diethyl 1-
Acetylene-1.4-butylene-bis-carbamate is obtained.

Claims (1)

[Claims] 1 formula (wherein n is an integer of 2 or 3) and pharmaceutically acceptable salts thereof. 2. The compound according to claim 1, which is 1-acetylene-1,4-butanediamine. 3. The compound according to claim 1, which is 1-acetylene-1,4-pentanediamine. 4 Treatment of an appropriately protected propargylamine derivative with a strong base generates a protected propargylamine carbanion intermediate, which is converted to PhHC=
NCH ₂ (CH ₂ )n-X (n is an integer of 2 or 3,
is a halogen) and then the protecting group is removed by hydrolysis, but the above alkylation is
The formula consists of carrying out in a neutral solvent for 1/2 to 24 hours at a temperature of 125 ° C to 25 ° C (wherein n is an integer of 2 or 3).